Derivation of Hydroquinone to Produce Selective, Oxidatively Activated Chemotherapeutic Agents

Derivation of Hydroquinone to Produce Selective, Oxidatively Activated Chemotherapeutic Agents

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Main Author: Bell-Horwath, Tiffany R.
Language:English
Published: University of Cincinnati / OhioLINK 2014
Subjects:
Biochemistry
Reactive Oxygen Species
AML
ROS
Anti-Cancer Agent
Drug Design
Acute Myeloid Leukemia
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406821452
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-ucin14068214522021-08-03T06:26:29Z Derivation of Hydroquinone to Produce Selective, Oxidatively Activated Chemotherapeutic Agents Bell-Horwath, Tiffany R. Biochemistry Reactive Oxygen Species AML ROS Anti-Cancer Agent Drug Design Acute Myeloid Leukemia DNA modifying agents are stalwarts of chemotherapeutic cancer treatments, but require vital design improvements to improve selectivity, lower side effects, and continue their widespread use. A key problem for DNA modifying agents is lack of specificity. To address this issue, our lab designs novel molecular scaffolds which are activated by a hallmark of some cancers: increased oxidative stress cause by reactive oxygen species (ROS).Oxidative stress, as measured by levels of ROS, oxidized biomolecules, and enzyme activity, is a hallmark of certain cancer cells. My work focuses on a potential path forward in the design of DNA modifying agents by exploiting the increased ROS into a pro-drug approach. Elevation of ROS has been linked to oncogenesis and has been found in several aggressive cancers, including renal cell carcinoma, melanoma, and leukemia. ROS occurs in four major endogenous forms within the cell: superoxide, hydrogen peroxide, singlet oxygen, and hydroxyl radical. ROS occur in cells via two discrete mechanisms; first, as a byproduct of metabolism. For example, mitochondria generate superoxide via complex I and III during oxidative phosphorylation. Secondly, ROS are known to derive from several enzymes. Especially important are NADPH oxidases that regulate the function of several tyrosine kinases involved in cell growth and survival. Amplified ROS results in increased DNA damage and mutation, tumor heterogeneity, the ability to self-replicate, and angiogenesis. In turn, these mutations cause enhanced activation of oncogenes. Consequently, it is no surprise that levels of ROS-induced DNA damage correlates with cancer prognosis. We utilize a design strategy wherein the pro-drug is stable, but upon ROS activation a reactive molecule is formed. This leads to more reactive forms of the molecule being present in cancer cells. Thus reactivity, and not uptake, is controlled to induce cytotoxicity more specifically in cancer cells and lower off-target reactions. 2014-10-17 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406821452 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406821452 unrestricted This thesis or dissertation is protected by copyright: some rights reserved. It is licensed for use under a Creative Commons license. Specific terms and permissions are available from this document's record in the OhioLINK ETD Center.
collection NDLTD
language English
sources NDLTD
topic Biochemistry
Reactive Oxygen Species
AML
ROS
Anti-Cancer Agent
Drug Design
Acute Myeloid Leukemia
spellingShingle Biochemistry
Reactive Oxygen Species
AML
ROS
Anti-Cancer Agent
Drug Design
Acute Myeloid Leukemia
Bell-Horwath, Tiffany R.
Derivation of Hydroquinone to Produce Selective, Oxidatively Activated Chemotherapeutic Agents
author Bell-Horwath, Tiffany R.
author_facet Bell-Horwath, Tiffany R.
author_sort Bell-Horwath, Tiffany R.
title Derivation of Hydroquinone to Produce Selective, Oxidatively Activated Chemotherapeutic Agents
title_short Derivation of Hydroquinone to Produce Selective, Oxidatively Activated Chemotherapeutic Agents
title_full Derivation of Hydroquinone to Produce Selective, Oxidatively Activated Chemotherapeutic Agents
title_fullStr Derivation of Hydroquinone to Produce Selective, Oxidatively Activated Chemotherapeutic Agents
title_full_unstemmed Derivation of Hydroquinone to Produce Selective, Oxidatively Activated Chemotherapeutic Agents
title_sort derivation of hydroquinone to produce selective, oxidatively activated chemotherapeutic agents
publisher University of Cincinnati / OhioLINK
publishDate 2014
url http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406821452
work_keys_str_mv AT bellhorwathtiffanyr derivationofhydroquinonetoproduceselectiveoxidativelyactivatedchemotherapeuticagents
_version_ 1719437047365632000

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